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Genes & Diseases Jul 2022Calcineurin (CaN) is a unique calcium (Ca) and calmodulin (CaM)-dependent serine/threonine phosphatase that becomes activated in the presence of increased intracellular... (Review)
Review
Calcineurin (CaN) is a unique calcium (Ca) and calmodulin (CaM)-dependent serine/threonine phosphatase that becomes activated in the presence of increased intracellular Ca level. CaN then functions to dephosphorylate target substrates including various transcription factors, receptors, and channels. Once activated, the CaN signaling pathway participates in the development of multiple organs as well as the onset and progression of various diseases via regulation of different cellular processes. Here, we review current literature regarding the structural and functional properties of CaN, highlighting its crucial role in the development and pathogenesis of immune system disorders, neurodegenerative diseases, kidney disease, cardiomyopathy and cancer.
PubMed: 35685477
DOI: 10.1016/j.gendis.2021.03.002 -
Kidney Diseases (Basel, Switzerland) Jan 2022Dual-specificity phosphatases (DUSPs) belong to the family of protein tyrosine phosphatases, which can dephosphorylate both serine/threonine and tyrosine residues.... (Review)
Review
BACKGROUND
Dual-specificity phosphatases (DUSPs) belong to the family of protein tyrosine phosphatases, which can dephosphorylate both serine/threonine and tyrosine residues. During the past decades, DUSPs have been implicated in various physiological and pathological activities. Besides mitogen-activated protein kinases (MAPKs) as the main substrates, other protein and nonprotein substrates can also be dephosphorylated by DUSPs. Aberrant regulations of DUSPs have been found in various diseases such as cancer, neurological disorders, and kidney diseases, suggesting the involvement of DUSPs in the pathogenesis of diseases.
SUMMARY
In this review, we summarize the general characteristics of DUSPs and the research progress made in the field of kidney diseases, including diabetic nephropathy, hypertensive nephropathy, chronic kidney disease, acute kidney injury, and lupus nephritis. As the main biochemical function of DUSPs is to dephosphorylate MAPKs activity, decreased DUSPs are found in kidney disease models, whereas forced DUSPs expression reverses the disease presentation, which was proved by using transgenic or gene knockout model.
KEY MESSAGES
Mounting evidence demonstrates that DUSPs have essential physiological and pathological functions in kidney disease. Fully understanding the functions and mechanisms of DUSPs in kidney disease contributes to their clinical application in translation medicine.
PubMed: 35224004
DOI: 10.1159/000520142 -
Frontiers in Plant Science 2022
PubMed: 36160988
DOI: 10.3389/fpls.2022.1020772 -
Frontiers in Cell and Developmental... 2021Like other biomolecules including nucleic acid and protein, glycan plays pivotal roles in various cellular processes. For instance, it modulates protein folding and... (Review)
Review
Like other biomolecules including nucleic acid and protein, glycan plays pivotal roles in various cellular processes. For instance, it modulates protein folding and stability, organizes extracellular matrix and tissue elasticity, and regulates membrane trafficking. In addition, cell-surface glycans are often utilized as entry receptors for viruses, including SARS-CoV-2. Nevertheless, its roles as ligands to specific surface receptors have not been well understood with a few exceptions such as selectins and siglecs. Recent reports have demonstrated that chondroitin sulfate and heparan sulfate, both of which are glycosaminoglycans, work as physiological ligands on their shared receptor, protein tyrosine phosphatase sigma (PTPσ). These two glycans differentially determine the fates of neuronal axons after injury in our central nervous system. That is, heparan sulfate promotes axonal regeneration while chondroitin sulfate inhibits it, inducing dystrophic endbulbs at the axon tips. In our recent study, we demonstrated that the chondroitin sulfate (CS)-PTPσ axis disrupted autophagy flux at the axon tips by dephosphorylating cortactin. In this minireview, we introduce how glycans work as physiological ligands and regulate their intracellular signaling, especially focusing on chondroitin sulfate.
PubMed: 34222264
DOI: 10.3389/fcell.2021.702179 -
Cell Reports May 2023The molecular and pathogenic mechanisms of esophageal squamous cell carcinoma (ESCC) development are still unclear, which hinders the development of effective...
The molecular and pathogenic mechanisms of esophageal squamous cell carcinoma (ESCC) development are still unclear, which hinders the development of effective treatments. In this study, we report that DUSP4 is highly expressed in human ESCC and is negatively correlated with patient prognosis. Knockdown of DUSP4 suppresses cell proliferation and patient-derived xenograft (PDX)-derived organoid (PDXO) growth and inhibits cell-derived xenograft (CDX) development. Mechanistically, DUSP4 directly binds to heat shock protein isoform β (HSP90β) and promotes the ATPase activity of HSP90β by dephosphorylating HSP90β on T214 and Y216. These dephosphorylation sites are critical for the stability of JAK1/2-STAT3 signaling and p-STAT3 (Y705) nucleus translocation. In vivo, Dusp4 knockout in mice significantly inhibits 4-nitrochinoline-oxide-induced esophageal tumorigenesis. Moreover, DUSP4 lentivirus or treatment with HSP90β inhibitor (NVP-BEP800) significantly impedes PDX tumor growth and inactivates the JAK1/2-STAT3 signaling pathway. These data provide insight into the role of the DUSP4-HSP90β-JAK1/2-STAT3 axis in ESCC progression and describe a strategy for ESCC treatment.
Topics: Animals; Humans; Mice; Cell Line, Tumor; Cell Proliferation; Dual-Specificity Phosphatases; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Gene Expression Regulation, Neoplastic; Heterografts; Mitogen-Activated Protein Kinase Phosphatases; Signal Transduction
PubMed: 37141098
DOI: 10.1016/j.celrep.2023.112445 -
Cold Spring Harbor Perspectives in... Mar 2020The tumor suppressor (PTEN) is a tightly regulated enzyme responsible for dephosphorylating the progrowth lipid messenger molecule phosphatidylinositol... (Review)
Review
The tumor suppressor (PTEN) is a tightly regulated enzyme responsible for dephosphorylating the progrowth lipid messenger molecule phosphatidylinositol 3,4,5-trisphosphate (PIP) on the plasma membrane. The carboxy-terminal tail (CTT) of PTEN is key for regulation of the enzyme. When phosphorylated, the unstructured CTT interacts with the phosphatase-C2 superdomain to inactivate the enzyme by preventing membrane association. PTEN mutations associated with cancer also inactivate the enzyme. Alternate translation-initiation sites generate extended isoforms of PTEN, such as PTEN-L that has multiple roles in cells. The extended amino-terminal region bears a signal sequence and a polyarginine sequence to facilitate exit from and entry into cells, respectively, and a membrane-binding helix that activates the enzyme. This amino-terminal region also facilitates mitochondrial and nucleolar localization. This review explores PTEN structure and its impact on localization and regulation.
Topics: Amino Acid Sequence; Humans; Mutation; Neoplasms; PTEN Phosphohydrolase; Phosphorylation
PubMed: 31636093
DOI: 10.1101/cshperspect.a036152 -
Molecular Cell Jan 2023In eukaryotes, cyclin-dependent kinase (CDK) ensures that the genome is duplicated exactly once by inhibiting helicase loading factors before activating origin firing....
In eukaryotes, cyclin-dependent kinase (CDK) ensures that the genome is duplicated exactly once by inhibiting helicase loading factors before activating origin firing. CDK activates origin firing by phosphorylating two substrates, Sld2 and Sld3, forming a transient and limiting intermediate-the pre-initiation complex (pre-IC). Here, we show in the budding yeast Saccharomyces cerevisiae that the CDK phosphorylations of Sld3 and Sld2 are rapidly turned over during S phase by the PP2A and PP4 phosphatases. PP2A targets Sld3 specifically through an Rts1-interaction motif, and this targeted dephosphorylation is important for origin firing genome-wide, for formation of the pre-IC at origins and for ensuring that Sld3 is dephosphorylated in G1 phase. PP2A promotes replication in vitro, and we show that targeted Sld3 dephosphorylation is critical for viability. Together, these studies demonstrate that phosphatases enforce the correct ordering of replication factor phosphorylation and in addition to kinases are also key drivers of replication initiation.
Topics: DNA-Binding Proteins; Saccharomyces cerevisiae Proteins; DNA Replication; Cyclin-Dependent Kinases; Cell Cycle Proteins; Phosphorylation; Saccharomyces cerevisiae; Saccharomycetales; Replication Origin
PubMed: 36543171
DOI: 10.1016/j.molcel.2022.12.001 -
Annual Review of Genetics Nov 2023Enzymes that phosphorylate, dephosphorylate, and ligate RNA 5' and 3' ends were discovered more than half a century ago and were eventually shown to repair purposeful... (Review)
Review
Enzymes that phosphorylate, dephosphorylate, and ligate RNA 5' and 3' ends were discovered more than half a century ago and were eventually shown to repair purposeful site-specific endonucleolytic breaks in the RNA phosphodiester backbone. The pace of discovery and characterization of new candidate RNA repair activities in taxa from all phylogenetic domains greatly exceeds our understanding of the biological pathways in which they act. The key questions anent RNA break repair in vivo are () identifying the triggers, agents, and targets of RNA cleavage and () determining whether RNA repair results in restoration of the original RNA, modification of the RNA (by loss or gain at the ends), or rearrangements of the broken RNA segments (i.e., RNA recombination). This review provides a perspective on the discovery, mechanisms, and physiology of purposeful RNA break repair, highlighting exemplary repair pathways (e.g., tRNA restriction-repair and tRNA splicing) for which genetics has figured prominently in their elucidation.
Topics: Phylogeny; RNA Ligase (ATP); RNA; RNA, Transfer; RNA Splicing
PubMed: 37722686
DOI: 10.1146/annurev-genet-071719-021856 -
The Biochemical Journal Mar 2021Adhesive structures between cells and with the surrounding matrix are essential for the development of multicellular organisms. In addition to providing mechanical... (Review)
Review
Adhesive structures between cells and with the surrounding matrix are essential for the development of multicellular organisms. In addition to providing mechanical integrity, they are key signalling centres providing feedback on the extracellular environment to the cell interior, and vice versa. During development, mitosis and repair, cell adhesions must undergo extensive remodelling. Post-translational modifications of proteins within these complexes serve as switches for activity. Tyrosine phosphorylation is an important modification in cell adhesion that is dynamically regulated by the protein tyrosine phosphatases (PTPs) and protein tyrosine kinases. Several PTPs are implicated in the assembly and maintenance of cell adhesions, however, their signalling functions remain poorly defined. The PTPs can act by directly dephosphorylating adhesive complex components or function as scaffolds. In this review, we will focus on human PTPs and discuss their individual roles in major adhesion complexes, as well as Hippo signalling. We have collated PTP interactome and cell adhesome datasets, which reveal extensive connections between PTPs and cell adhesions that are relatively unexplored. Finally, we reflect on the dysregulation of PTPs and cell adhesions in disease.
Topics: Animals; Cell Adhesion; Cell Adhesion Molecules; Humans; Protein Tyrosine Phosphatases
PubMed: 33710332
DOI: 10.1042/BCJ20200511 -
Frontiers in Cell and Developmental... 2022In most animal cell types, the interphase nucleus is largely disassembled during mitotic entry. The nuclear envelope breaks down and chromosomes are compacted into... (Review)
Review
In most animal cell types, the interphase nucleus is largely disassembled during mitotic entry. The nuclear envelope breaks down and chromosomes are compacted into separated masses. Chromatin organization is also mostly lost and kinetochores assemble on centromeres. Mitotic protein kinases play several roles in inducing these transformations by phosphorylating multiple effector proteins. In many of these events, the mechanistic consequences of phosphorylation have been characterized. In comparison, how the nucleus reassembles at the end of mitosis is less well understood in mechanistic terms. In recent years, much progress has been made in deciphering how dephosphorylation of several effector proteins promotes nuclear envelope reassembly, chromosome decondensation, kinetochore disassembly and interphase chromatin organization. The precise roles of protein phosphatases in this process, in particular of the PP1 and PP2A groups, are emerging. Moreover, how these enzymes are temporally and spatially regulated to ensure that nuclear reassembly progresses in a coordinated manner has been partly uncovered. This review provides a global view of nuclear reassembly with a focus on the roles of dephosphorylation events. It also identifies important open questions and proposes hypotheses.
PubMed: 36268509
DOI: 10.3389/fcell.2022.1012768